Colorectal carcinoma is largely preventable through the use of screening and removal of precursor lesion, adenomas. Although colonoscopy is the most commonly used screening test, recent studies have cast senous doubt about its effectiveness in preventing right sided cancer. Furthermore, there is a significant proportion of eligible patients who decline colonoscopy or in whom colonoscopy is not readily available. Testing for aberrant molecular/genetic markers in stool DNA (sDNA) is emerging as a promising alternative to colonoscopy. The currently available sDNA test detects aberrant methylation of the vimentin gene and has reported an 80-85% sensitivity for the detection of colorectal carcinoma. A newly developed next-generation sDNA test with 3 additional methylated DNA markers that are complementary to vimentin promises to be more sensitive and specific. However, these newer markers have not been validated in a screening population and data on the efficacy of sDNA testing for advanced adenomas, hence prevention of colorectal cancer, are limited. Therefore, we propose a prospective screening study to systematically evaluate the accuracy and clinical relevance of this multi-marker panel sDNA testing for detecting advanced adenomas. Specifically, our study aims to: 1) evaluate the performance characteristics of sDNA testing and compare that to the fecal immunochemical test (FIT) for the detection of advanced adenomas in an asymptomatic average-risk screening population; 2) determine the concordance/discordance between tissue and stool gene aberrant methylation in patients with advanced adenomas; 3) investigate the persistence of positive sDNA testing after removal of advanced adenomas; and 4) assess the frequency of missed or occult colonic and upper gastrointestinal neoplasia in patients with a normal colonoscopy but persistently positive sDNA testing. These aims will be accomplished in a comparative study of 1,600 average risk patients undergoing screening colonoscopy. This project is highly translational and information gained from this study may have significant and immediate implication for the clinical practice of screening and primary prevention of colorectal cancer, and surveillance of patients with advanced adenomas.